SCN5A (Nav1.5): Predicting the Consequence of Missense Single- Nucleotide Polymorphisms.
SCN5A (Nav1.5):预测错义单核苷酸多态性的后果。
基本信息
- 批准号:9224146
- 负责人:
- 金额:$ 12.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-15 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAlgorithmsAmino Acid SequenceAmino AcidsApicalAwardBenignBiological ModelsBiologyBrugada syndromeCRISPR/Cas technologyCardiacCardiac MyocytesCell surfaceCellsCharacteristicsChemistryChloridesClinicalCollaborationsComputer SimulationDataData SetDefectDilated CardiomyopathyDisciplineDiscriminationDiseaseEducationElectrophysiology (science)EnvironmentEquilibriumEstrogensEvaluationFamilyFluorescence-Activated Cell SortingFoundationsGenesGenetic VariationGenomic medicineGoalsHeart DiseasesHip region structureHumanInduced MutationIon ChannelLaboratoriesLearningLinkLiteratureLong QT SyndromeMembrane ProteinsMentorsMethodsMissense MutationModelingMutationNatureNoiseNuclear Magnetic ResonanceOutputPathogenicityPenetrancePhasePhenotypePoint MutationPostdoctoral FellowProductionProteinsRecoveryResearchResearch PersonnelResearch Project GrantsResourcesRisk FactorsSchoolsScientistSick Sinus SyndromeSignal TransductionSingle Nucleotide PolymorphismSodiumSodium ChannelSpectrum AnalysisStructureSyndromeTechniquesTechnologyTestingTimeTrainingTranslational ResearchTransmembrane DomainUniversitiesValidationVariantVirginiabasecareer developmentclinical Diagnosisdensityflexibilitygenetic variantgenomic profileshuman diseaseimprovedinduced pluripotent stem cellinstrumentmolecular dynamicsnext generation sequencingpersonalized medicineprediction algorithmpredictive modelingpreventprofiles in patientsprotein functionprotein structureskillsstructural biologytooltraffickingundergraduate studentvariant of unknown significancevoltage
项目摘要
Project Summary/Abstract
Candidate Background: In graduate school at the University of Virginia, I built on my undergraduate
spectroscopy education by using spectroscopic tools to investigate membrane protein flexibility. As a
Postdoctoral Fellow at Vanderbilt, I transitioned to membrane protein structural biology involved in human
disease, specifically KCNQ and KCNE family-associated channelopathies. As a Postdoctoral Fellow, I have
been involved in several projects concerning the structural underpinnings of disease mechanisms, most recently
proposing a mechanism for diminished apical chloride secretion through an estrogen-induced loss of KCNQ1-
KCNE3 channel conduction.
Research Strategy: The human voltage-gated sodium channel Nav1.5 (encoded by SCN5A) is implicated in
several diseases of the heart including dilated cardiomyopathy, cardiac conduction disease, sick sinus syndrome,
type 3 longQT syndrome, and Brugada syndrome. Several algorithms accurately predict SCN5A variants that
are ultimately harmful (SIFT, PolyPhen-2, PredSNP, etc.). However, there is a significant gap in the negative
predictive ability of these methods, i.e. the ability to accurately classify a variant as benign. The approach I am
proposing is to tackle this problem on two fronts: 1) incorporating channel-specific, quantitative information-rich
data into predictive model construction—the objective being to predict channel function, instead of disease-
inducing propensity—and 2) including a set of point mutation variants enriched in WT/neutral phenotypes to
improve discrimination power during model training and evaluation. This project aims to ultimately predict Nav1.5
channel phenotypes for all possible amino-acid changing single nucleotide polymorphisms (nsSNP) by balancing
high-throughput computation and rigorous experimental validation with model systems: predicting the nearly
15,000 possible SCN5A missense nsSNPs is currently only feasible in silico, i.e. leveraging calculable
channel-specific protein sequence and structure-based features. The availability of a high-throughput
electrophysiology instrument allows for an unprecedented amassing of ion channel functional output from
heterologously expressed Nav1.5; the evaluation of SCN5A variants impact on action potential in the more native
like human induced pluripotent stem cell cardiomyocytes is possible in low-throughput. During the mentored
(K99) phase of this award, I will generate (mis)trafficking and electrophysiology current output data from
missense nsSNPs of SCN5A, focusing on the Voltage-Sensing Module (VSM) of domain IV (Aim 1) and train an
SCN5A VSM IV-specific phenotype prediction model using trafficking and electrophysiology data from Aim 1 and
the literature (Aim 2). As an independent investigator, I will determine structure and flexibility-induced changes
from selected variants using a combination of Rosetta modeling and nuclear magnetic resonance (NMR) to refine
the predictive model (Aim 3).
Career Development and Training: My training proposal is ambitious covering several disciplines, some of
which will be new to me. The skills I will acquire are developing computational predictive models of ion channel
phenotypes, trafficking/expression quantitation through Fluorescence Activated Cell Sorting (FACS),
CRISPR/Cas9 gene manipulation, and hiPSC cardiomyocyte production. Though there are many activities
planned, I will be trained directly in the laboratories of prominent scientists in their respective fields: Charles
Sanders, Jens Meiler, and Dan Roden.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brett M Kroncke其他文献
Brett M Kroncke的其他文献
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{{ truncateString('Brett M Kroncke', 18)}}的其他基金
Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance
整合 KCNH2 变体特异性特征和杂合子表型来估计长 QT 外显率
- 批准号:
10557122 - 财政年份:2022
- 资助金额:
$ 12.25万 - 项目类别:
Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance
整合 KCNH2 变体特异性特征和杂合子表型来估计长 QT 外显率
- 批准号:
10343134 - 财政年份:2022
- 资助金额:
$ 12.25万 - 项目类别:
Structural rationale for open-state-inducing mutation in human Iks-producing potassium channel complex
产生人 Iks 的钾通道复合物中开放态诱导突变的结构原理
- 批准号:
8834238 - 财政年份:2015
- 资助金额:
$ 12.25万 - 项目类别:
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